APOL6 predicts immunotherapy efficacy of bladder cancer by ferroptosis

Abstract

Abstract Background Immune checkpoint inhibitors (ICIs) are rapidly evolving in the management of bladder cancer (BLCA). Nevertheless, effective biomarkers for predicting immunotherapeutic outcomes in BLCA are still insufficient. Ferroptosis, a form of immunogenic cell death, has been found to enhance patient sensitivity to ICIs. However, the underlying mechanisms of ferroptosis in promoting immunotherapy efficacy in BLCA remain obscure. Methods Our analysis of The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) revealed two immunologically distinct subtypes. Based on these subtypes and various other public cohorts, we identified Apolipoprotein L6 (APOL6) as a biomarker predicting the efficacy of ICIs and explored its immunological correlation and predictive value for treatment. Furthermore, the role of APOL6 in promoting ferroptosis and its mechanism in regulating this process were experimentally validated. Results The results indicate that APOL6 has significant immunological relevance and is indicative of immunologically hot tumors in BLCA and many other cancers. APOL6, interacting with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), mediates immunotherapy efficacy by ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1). Conclusions To conclude, our findings indicate APOL6 has potential as a predictive biomarker for immunotherapy treatment success estimation and reveal the STAT1/APOL6/GPX4 axis as a critical regulatory mechanism in BLCA.

Keywords

• APOL6
• Bladder cancer (BLCA)
• Immunotherapy
• Ferroptosis